A transdermal delivery system is a pharmaceutical composition of matter which is applied to the skin in order to deliver the pharmaceutical through the skin to achieve a systemic therapeutic effect as distinguished from a local therapeutic effect.
If a drug exhibits transdermal fluxes that are too low to provide therapeutic plasma concentrations, a flux enhancer may be used to increase transdermal flux. The flux enhancer is a substance, usually a solvent or vehicle that is applied to the skin in combination with a drug to increase the transdermal flux of the drug. Flux enhancers are also known as percutaneous absorption promoters; flux promoters or permeation enhancers. Enhancers are believed to function by disrupting the barrier of the skin or by changing the partitioning behavior of the drug in the skin. In general, an enhancer is specific for a particular type of drug and it may not be useful with every drug. Japanese published patent application No. 59-23673 of Feb. 10, 1984, discloses the use of substances such as propylene glycol, triethylene glycol, polyethylene glycols, ethyl alcohol, salicylic acid, dimethyl sulfoxide, dimethyl acetamide, urea, diethyl sebacate, propylene carbonate, N-methyl pyrrolidone, lanolin or mineral oil components of a transermal delivery systems for dihydro pyridines. Japanese published patent application No. 59-251037 of Nov. 27, 1984, discloses the use of certain pyrrolidones and imidazolinones as transcutaneous flux enhancers for 1,4-dihydropyridine derivatives.
Japanese published patent application No. 59-175415 describes various absorption promoting agents for nifedipine. These agents include lanolin, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dodecyl bromide and diethyl sebacate. Japanese published patent application No. 58-177916 discloses the topical use of solvents such as benzyl benzoate, diisopropyl adipate, benzyl alcohol, N-methyl-2-pyrrolidone and crotamitnon for nifedipine and nicardipine. Japanese published patent application No. 59-39827 discloses the topical administration of nifedipine using auxiliary substances such as propylene glycol, ethylene glycol, ethanol, salicylic acid, urea dimethyl acetamide, dimethyl formamide, diethyl sebacate, lanolin and various surface active agents.
Applicants' have now surprisingly discovered that the transdermal flux rate of certain 1,4-dihydropyridine derivatives of the formula ##STR1## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are hereafter defined, may be increased by the use of solvent vehicles consisting of esters of C.sub.12 -C.sub.18 fatty acids with C.sub.1 -C.sub.6 straight and branched chain alcohols; diesters of aliphatic diacids of the formula EQU R.sub.8 OOC(CH.sub.2).sub.n COO R.sub.9
wherein n is a whole integer from 2-8; R.sub.8 and R.sub.9 may be the same or different and are selected from the group consisting of C.sub.2 to C.sub.12 straight and branched chain alcohols; and compounds of the formula ##STR2## wherein R.sub.10 is a C.sub.7 -C.sub.13 alkyl or alkenyl group R.sub.11 and R.sub.12 are the same or different and are selected from --CH.sub.2 CH.sub.2 OH and --CH.sub.2 CH.sub.2 CH.sub.2 --OH; benzyl alcohol, 2-phenylethanal or mixtures thereof with ethyl alcohol.